1. Field of the Invention
The present invention relates to a method for the treatment of mammalian retrovirus infections, such as human immunodeficiency virus (HIV), using combinations of retroviral protease inhibitors which are effective in preventing the replication of mammalian retroviruses, like HIV, in vitro and in vivo. This invention, in particular, relates to protease inhibitor compounds used in combination therapy with other protease inhibitor compounds.
2. Related Art
During the replication cycle of retroviruses, gag and gag-pol gene transcription products are translated as proteins. The proteins are subsequently processed by a virally encoded protease (or proteinase) to yield viral enzymes and structural proteins of the virus core. Most commonly, the gag precursor proteins are processed into the core proteins and the pol precursor proteins are processed into the viral enzymes, e.g., reverse transcriptase and retroviral protease. It has been shown that correct processing of the precursor proteins by the retroviral protease is necessary for assembly of infectious virons. For example, it has been shown that frameshift mutations in the protease region of the pol gene of HIV prevents processing of the gag precursor protein. It has also been shown through site-directed mutagenesis of an aspartic acid residue in the HIV protease active site that processing of the gag precursor protein is prevented. Thus, attempts have been made to inhibit viral replication by inhibiting the action of retroviral proteases.
Retroviral protease inhibition typically involves a transition-state mimetic whereby the retroviral protease is exposed to a mimetic compound which binds (typically in a reversible manner) to the enzyme in competition with the gag and gag-pol proteins to thereby inhibit specific processing of structural proteins and the release of retroviral protease itself. In this manner, retroviral replication proteases can be effectively inhibited.
Several classes of mimetic compounds have been proposed, particularly for inhibition of proteases, such as for inhibition of HIV protease. Such mimetics include hydroxyethylamine isosteres, reduced amide isosteres and non-peptide isosteres. See for example, EP 0 346 847; EP 0 342 541; Roberts et al, "Rational Design of Peptide-Based Proteinase Inhibitors," Science, 248, 358 (1990); Erickson et al, "Design Activity, and 2.8 .ANG. Crystal Structure of a C.sub.2 Symmetric Inhibitor Complexed to HIV-1 Protease," Science, 249, 527 (1990); and S. Thaisrivongs, "Structure-Based Design of Non-Peptide HIV Protease Inhibitors," 35th Annual Buffalo Medicinal Chemistry Meeting, State University of New York at Buffalo, Buffalo, N.Y., May 22-25, 1994.
A problem for retroviral protease inhibitors, like HIV protease inhibitors, has been the development of strains of the virus resistant to the inhibitor. For example, Merck & Co.'s HIV protease inhibitor L-735,524 is effective against HIV infections in humans, but L-735,524 resistant strains of HIV later develop in patients (Waldholz, The Wall Street Journal, Feb. 25, 1994, page B3; and Condra et al., Nature 374:569-571 (1995)). Other examples can be found in Vacca et al., Proc. Natl. Acad. Sci. USA 91:4096-4100 (1994); Ho et al., J. Virol. 68:2016-2020 (1994); and Sardana et al., Biochem. 33:2004-2010 (1994).